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12 mcg/kg/day on Days 1 through 4 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks)

Drug: Denileukin diftitox

Test product: dose and mode of administration:

denileukin diftitox was originally administered by intravenous infusion over 30-60 minutes according to 1 of 2 treatment arms:

12 mcg/kg/day on Days 1 through 4 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks);

12 mcg/kg/day on Days 1, 8, and 15 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks)

ARM 2 is now closed. Patients experiencing clinical benefit (irSD, irPR, or irCR per irRC) after 4 cycles of treatment, may continue their denileukin diftitox treatment for up to 8 cycles.

Detailed Description:

This is a multicenter, open-label, dose/schedule and clinical efficacy study in patients with Stage IIIC and Stage IV melanoma.

Dose-Schedules: This is a schedule, dose, and pharmacodynamic study of Denileukin diftitox in in patients with Stage IIIC and Stage IV melanoma. Two arms of 40 patients each were originally planned (see below) for a total of 80 patients. Patients were randomly assigned to 1 of 2 arms: 1. 12 mcg/kg/day on Days 1 through 4 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks); 2. 12 mcg/kg/day on Days 1, 8, and 15 of each 21-day treatment cycle, for a total of 4 cycles (12 weeks). Patients will be evaluated for (clinical response, safety and tolerability, and pharmacodynamic measures of ONTAK activity. An optional substudy will be conducted that will involve collection of serial tumor biopsies at study entry and Day 84 in order to assess tissue pharmacodynamic markers of ONTAK activity (Treg depletion in tumor, appearance of melanoma antigen-specific CD8+lymphocytes, and other markers of mucosal immunity and inflammatory response).

Following an amendment, patients will be enrolled in Arm 1 only (expanded to a total of 55 patients) and Arm 2 was closed. According to the original design, if two responses or less were observed among 22 patients on either arm, that arm would be discontinued.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria Patients may be entered in the study only if they meet all of the following criteria.

At least 1 site of radiographically measurable disease by immune-related response criteria (irRC);

Serum albumin greater than or equal to 3 g/dL;

Adequate hematologic, renal, and liver function as defined by laboratory values performed within 21 days prior to initiation of dosing:

Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L;

Platelet count greater than or equal to 100 x 10^9/L;

Hemoglobin greater than or equal to 9 g/dL;

Serum creatinine less than or equal 1.5 x upper limit of normal (ULN) or creatinine clearance greater than or equal to 50 mL/min;

Total serum bilirubin less than or equal to 1.5 x ULN;

Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) less than or equal to 2.5 x ULN, and less than or equal to 5 x ULN if liver metastases are present.

Fertile males should use an effective method of contraception during treatment and for at least 3 months after completion of treatment, as directed by their physician;

Pre-menopausal females and females less than 2 years after the onset of menopause should have a negative pregnancy test at Screening. Pre-menopausal females must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Females of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for greater than or equal to 1 year; Before study entry, written informed consent must be obtained from the patient prior to performing any study-related procedures.

Treated brain metastases are defined as having no evidence of progression or hemorrhage for 2 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computerized tomography [CT]) during the Screening period (using the pretreatment brain image as Baseline). Treatment for brain metastases must have been completed at least 2 months prior to Day 1 of the first treatment cycle and may include whole brain radiotherapy, radiosurgery (Gamma Knife, LINAC, or equivalent), or a combination as deemed appropriate by the treating physician. Dexamethasone must be discontinued at least 4 weeks prior to Day 1. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 months prior to Day 1 will be excluded;

Carcinomatous meningitis;

Prior treatment with denileukin diftitox;

Known hypersensitivity to denileukin diftitox or any of its components: diphtheria toxin, IL-2, or excipients;

Prior surgery for melanoma less than 4 weeks before enrollment;

Other malignancy within 3 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence and/or malignancies diagnosed at a stage where definitive therapy results in near certain cures. The Medical Monitor must be consulted in such cases;

Currently receiving any other anticancer treatment for melanoma (including palliative radiotherapy);

Received treatment in another clinical study within the 4 weeks prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Common Terminology Criteria for Adverse Events (CTCAE) Grade less than or equal to 1, except for alopecia;

Received radiotherapy for non-CNS disease within the 2 weeks prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to Grade less than or equal to 1, except for alopecia;

Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives, or avoidance of pregnancy measures; Have any other uncontrolled infection or medical condition that could interfere with the conduct of the study.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01127451